Defects in potassium cycling, gap junction-mediated intercellular communication and cochlear metabolism are re-sponsible for the over whelming majority of hearing impairments This proposal is designed to further our under-standing of potassium cycling, by determining the role of connexins in potassium cycling, glutamate metabolism and the prevention of apoptosis and to determine whether a monocarboxylate shuttle contributes to meet the energetic needs of the cochlea. In detail, under Specific Aim 1, we will define the path of potassium cycling that leads from the hair cells in the organ of Corti to strial marginal cells in stria vascularis. Under Specific Aim 2, we will detelmine the subunit composition of the potassium channels KCNQ1 in strial marginal cells, KCNQ4 in outer hair cells and KCNJ10 in strial intermediate cells. These potassium channels are associated with hereditary forms of deafness KCNQ1 mediates potassium secretion into endolyinph, KCNQ4 mediates potassium release out of outer hair cells and KCNJ10 generates the endocochlear potentia. Each of these potassium channels is thus a major contributor to potassium cycling. Under Specific Aim 3, we will determine the role of connexins in glutamate metabolism and the prevention of apoptosis We hypothesize that glutamate metabolism in the organ of Corti is obligatorily dependent on connexin-mediated intracellular communication and that connexin hemichannels in supporting cells limit glutamate release from the inner hair cells. We will determine whether the capacity to metabolize glutamate is reduced by disruption of connexin-mediated intercellular communication and whether glutamate-induced metabolic stress causes opening of the mitochondrial permeability transition pore to initiate apoptosis. Finally, under Specific Aim 4, we propose to test the hypothesis that a monocarboxylate shuttle based in stria vascularis contributes to meet the metabolic needs of the organ of Corti. The completion of these studies will further our understanding of cochlear metabolism and homeostasis and provide a basic understanding of the molecular mechanisms that initiate the irreversible loss of sensory function in the inner ear.